Patients with advanced melanoma that is of low tumor‐associated antigen (TAA) expression often respond poorly to PD‐1/PD‐L1 blockade therapy. Epigenetic modulators, such as hypomethylation agents ...(HMAs), can enhance the antitumor immune response by inducing TAA expression. Here, a dual bioresponsive gel depot that can respond to the acidic pH and reactive oxygen species (ROS) within the tumor microenvironment (TME) for codelivery of anti‐PD1 antibody (aPD1) and Zebularine (Zeb), an HMA, is engineered. aPD1 is first loaded into pH‐sensitive calcium carbonate nanoparticles (CaCO3 NPs), which are then encapsulated in the ROS‐responsive hydrogel together with Zeb (Zeb‐aPD1‐NPs‐Gel). It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, and also plays roles in reversing immunosuppressive TME, which contributes to inhibiting the tumor growth and prolonging the survival time of B16F10‐melanoma‐bearing mice.
A dual bioresponsive drug delivery depot is engineered, which can respond to the acidic pH and reactive oxygen species within the tumor microenvironment (TME), for codelivery of anti‐PD1 antibody and Zebularine, an epigenetic modulator. It is demonstrated that this combination therapy increases the immunogenicity of cancer cells, reverses immunosuppressive TME, and enhances the antitumor immune response.
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•ZnO was synthesized from ZIF-8 template and also by direct calcination of Zn(NO3)2.•ZnOs were investigated for photo- and electrocatalytic oxidation of methylene blue.•Detailed ...mechanistic pathway was probed.•The cytotoxicity of methylene blue over melanoma cells was evaluated.
Due to the severe water pollution from effluent dyes, the need of the hour is to find a suitable dye degradation technology, and appropriate catalyst materials. Semiconducting ZnO was produced by pyrolysis of ZIF-8 template. The materials were well characterized with in situ and ex situ XRD and TGA, FE-SEM, HRTEM, UV-DRS, PL, and FRET. The results showed that upon calcination the body centered cubic ZIF-8 produces hexagonal primitive ZnO while retaining the truncated cubic shaped particles. The materials were screened for photo- and electro-catalytic oxidation of methylene blue. In both the different degradation technologies, ZnO synthesized from ZIF-8 outperformed the ZIF-8. The FRET dynamics showed significant spectral overlap of ZnO emission and the methylene blue absorption. It was found to be responsible for the better photocatalytic efficacy of ZnO samples than ZIF-8. The proposed reaction mechanism showed that the surface-bound reactive oxygen species produced either by light exposure or due to applied bias is key to dye degradation. The cytotoxicity of the untreated and ZnO and ZIF-8 treated dye over melanoma cells was evaluated, and it was found that the cytotoxicity of the degraded dye from ZIF-derived ZnO was less compared to that of ZIF-8 treated one.
•Indocyanine green is a photosensitizer approved for clinical use.•Anionic indocyanine green is unstable and hardly permeates through skin.•Topical photodynamic therapy is noninvasive strategy for ...melanoma treatment.•Chitosan-coating of liposomes can protect indocyanine green from degradation.•Chitosan-coated liposomes enhances skin permeation of indocyanine green.
Indocyanine green (ICG) has been used clinically and noticed as a promising candidate for the topical melanoma photodynamic therapy (PDT). Despite its high potentials in topical PDT, the use of ICG has been hampered by the instability in aqueous solution. In the present study, chitosan-coated liposomes were adopted as a formulation strategy which could stabilize and enhance skin permeation of ICG. Chitosan-coating was verified by the significantly increased liposomal size and reversed zeta potential from negative to positive value by positive chitosan coating. Chitosan-coating liposomes protected ICG from degradation while uncoated liposomes did not. Moreover, they significantly increased cellular uptake and photocytotoxicity of ICG in B16-F10 melanoma cells in a chitosan-dependent manner. The skin permeation of ICG was also drastically improved by chitosan-coated liposomes. These findings emphasize the promising potential of ICG-loaded chitosan-coated liposomes for topical PDT of melanoma.
The use of microneedles has facilitated the painless localized delivery of drugs across the skin. However, their efficacy has been limited by slow diffusion of molecules and often requires external ...triggers. Herein, an autonomous and degradable, active microneedle delivery platform is introduced, employing magnesium microparticles loaded within the microneedle patch, as the built‐in engine for deeper and faster intradermal payload delivery. The magnesium particles react with the interstitial fluid, leading to an explosive‐like rapid production of H2 bubbles, providing the necessary force to breach dermal barriers and enhance payload delivery. The release kinetics of active microneedles is evaluated in vitro by measuring the amount of IgG antibody (as a model drug) that passed through phantom tissue and a pigskin barrier. In vivo experiments using a B16F10 mouse melanoma model demonstrate that the active delivery of anti‐CTLA‐4 (a checkpoint inhibitor drug) results in greatly enhanced immune response and significantly longer survival. Moreover, spatially resolved zones of active and passive microneedles allow a combinatorial rapid burst response along with slow, sustained release, respectively. Such versatile and effective autonomous dynamic microneedle delivery technology offers considerable promise for a wide range of therapeutic applications, toward a greatly enhanced outcome, convenience, and cost.
An autonomous and degradable active microneedle delivery platform obviating external stimuli is presented. Active microneedles employ entrapped magnesium microparticles as built‐in engines capable of generating vigorous convective fluid flows for deeper and faster intradermal payload delivery. The “built‐in” active delivery strategy holds considerable promise for transdermal biomedical applications offering an attractive efficient delivery route compared to traditional passive microneedle patches.
Immunotherapy has exhibited enormous practice in the treatment of melanoma because of the intrinsic properties of tumor. Tumor can downmodulate immune function via multiple mechanisms such as immune ...checkpoint pathways. The PD-L1 monoclonal antibodies that block the PD1/PD-L1 pathway, which induced tumor cells to evade an immune attack, can delay tumor growth efficiently with inevitable disadvantages such as low selectivity and systemic toxicity. Nanomedicine is clearly an approach that holds tremendous potential for addressing the shortcomings and assisting delivery of drugs with proper biodistribution. Herein, we developed a smart nanoplatform with precisely active targeting liposome co-loaded chemotherapy and immunotherapy drugs for synergistic antitumor effects while decreasing systemic toxicity. Immunoliposomes have stable pharmaceutical properties and show a significant antitumor effect in vivo and in vitro. Cellular uptake in vitro and biodistribution in vivo demonstrated that immunoliposomes could be delivered and accumulated more in tumor tissues. These immunoliposomes exhibited effective tumor inhibition and prolonged survival time due to activation of tumor-specific CD8+ T cell and highly selective tumor killing. In addition, safety evaluation of liposomes also demonstrated their increased tumor accumulation and decreased systemic toxicity. Hence, this smart pH-sensitive nanoplatform has promising potential for clinical applications and possibly provides a well-controlled design for combination of chemotherapy with various immunotherapies for further exploration.
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•Preparation of immunoliposomes that co-loaded DTX and PD-L1 antibody•Immunoliposomes show precisely active targeting and effective therapeutic effect•Killing tumor cell directly while switching off immunosuppression•Increased tumor accumulation and decreased systemic toxicity by nanotechnology
•Marine macroalgae derived compounds are potential therapeutic agents in dermatology.•Seaweed extracts has been shown to protect skin from photo-damage.•Antibacterial compounds derived from ...macroalgae can fight acne and chronic wounds.•Anti-tumor activity of macroalgae extracts can be exploited to treat melanoma.•Skin whitening and anti-pigmentation properties of seaweed extracts are also discussed.
Functional components extracted from algal biomass are widely used as dietary and health supplements with a variety of applications in food science and technology. In contrast, the applications of algae in dermal-related products have received much less attention, despite that algae also possess high potential for the uses in anti-infection, anti-aging, skin-whitening, and skin tumor treatments. This review, therefore, focuses on integrating studies on algae pertinent to human skin care, health and therapy. The active compounds in algae related to human skin treatments are mentioned and the possible mechanisms involved are described. The main purpose of this review is to identify serviceable algae functions in skin treatments to facilitate practical applications in this high-potential area.
Endogenous retroviruses (ERVs) are remnants of ancient retroviral infections, and comprise nearly 8% of the human genome. The most recently acquired human ERV is HERVK(HML-2), which repeatedly ...infected the primate lineage both before and after the divergence of the human and chimpanzee common ancestor. Unlike most other human ERVs, HERVK retained multiple copies of intact open reading frames encoding retroviral proteins. However, HERVK is transcriptionally silenced by the host, with the exception of in certain pathological contexts such as germ-cell tumours, melanoma or human immunodeficiency virus (HIV) infection. Here we demonstrate that DNA hypomethylation at long terminal repeat elements representing the most recent genomic integrations, together with transactivation by OCT4 (also known as POU5F1), synergistically facilitate HERVK expression. Consequently, HERVK is transcribed during normal human embryogenesis, beginning with embryonic genome activation at the eight-cell stage, continuing through the emergence of epiblast cells in preimplantation blastocysts, and ceasing during human embryonic stem cell derivation from blastocyst outgrowths. Remarkably, we detected HERVK viral-like particles and Gag proteins in human blastocysts, indicating that early human development proceeds in the presence of retroviral products. We further show that overexpression of one such product, the HERVK accessory protein Rec, in a pluripotent cell line is sufficient to increase IFITM1 levels on the cell surface and inhibit viral infection, suggesting at least one mechanism through which HERVK can induce viral restriction pathways in early embryonic cells. Moreover, Rec directly binds a subset of cellular RNAs and modulates their ribosome occupancy, indicating that complex interactions between retroviral proteins and host factors can fine-tune pathways of early human development.
Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in ...vivo in a manner that is effective, facile, and amenable for clinical translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides. ND-MPLA/CpG significantly enhanced activation of dendritic cells, compared with free dual adjuvants or nanodiscs delivering a single TLR agonist. Importantly, mice immunized with physical mixtures of protein antigens ND-MPLA/CpG generated strong humoral responses, including induction of IgG responses against protein convertase subtilisin/kexin 9 (PCSK9), leading to 17–30% reduction of the total plasma cholesterol levels. Moreover, ND-MPLA/CpG exerted strong anti-tumor efficacy in multiple murine tumor models. Compared with free adjuvants, ND-MPLA/CpG admixed with ovalbumin markedly improved antigen-specific CD8+ T cell responses by 8-fold and promoted regression of B16F10-OVA melanoma (P < 0.0001). Furthermore, ND-MPLA/CpG admixed with E7 peptide antigen elicited ~20% E7-specific CD8+ T cell responses and achieved complete regression of established TC-1 tumors in all treated animals. Taken together, our work highlights the simplicity, versatility, and potency of dual TLR agonist nanodiscs for applications in vaccines and cancer immunotherapy.
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SF3B1 is the most commonly mutated RNA splicing factor in cancer
, but the mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here we integrated pan-cancer splicing ...analyses with a positive-enrichment CRISPR screen to prioritize splicing alterations that promote tumorigenesis. We report that diverse SF3B1 mutations converge on repression of BRD9, which is a core component of the recently described non-canonical BAF chromatin-remodelling complex that also contains GLTSCR1 and GLTSCR1L
. Mutant SF3B1 recognizes an aberrant, deep intronic branchpoint within BRD9 and thereby induces the inclusion of a poison exon that is derived from an endogenous retroviral element and subsequent degradation of BRD9 mRNA. Depletion of BRD9 causes the loss of non-canonical BAF at CTCF-associated loci and promotes melanomagenesis. BRD9 is a potent tumour suppressor in uveal melanoma, such that correcting mis-splicing of BRD9 in SF3B1-mutant cells using antisense oligonucleotides or CRISPR-directed mutagenesis suppresses tumour growth. Our results implicate the disruption of non-canonical BAF in the diverse cancer types that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.
Melanoma remains one of the most challenging malignant tumor related deaths worldwide and alternative approaches to efficiently treat melanoma are eagerly needed. Anti-PD1 antibody (aPD1) ...immunotherapy is the most significant and impactful therapy for melanoma by immune checkpoint inhibition and T cell stimulation to mediate tumor killing. But the clinical remission rate of aPD1 immunotherapy is limited in melanoma. Here we show a potent combination of aPD1 and photothermal therapy (PTT) by effective delivery of a multifunctional phase-transformation nanocarrier to melanoma tumor. We successfully synthesized multifunctional nanoparticles (NPs) encapsulated with aPD1, iron oxide and perfluoropentane (PFP) in lactic-co-glycolic acid (PLGA) shell modified with poly ethylene glycol (PEG) and Gly-Arg-Gly-Asp-Ser (GRGDS) peptides (GOP@aPD1). In vitro, GOP@aPD1 NPs were characterized for particle size and drug-loading efficiency. The NPs were also tested for photothermal property, optical droplet vaporization (ODV) capacity and the ability of aPD1 release profile. In vivo, GOP@aPD1 NPs were systemically administered to melanoma-bearing mice demonstrated no toxicity and accumulation at tumor site. When mediated with PTT, this synergistic treatment achieved enhanced antitumor efficacy, due to combination of the effective aPD1 release and increased CD8+ T cell infiltration in tumor site. In conclusion, GOP@aPD1 NPs combined with PTT could potentiate the efficacy of aPD1 not only by tumor-targeted delivery of aPD1 but also by activating the immune system in the tumor microenvironment, which is a highly effective approach to treat melanoma.
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•PTT-mediated phase-transformation nanoparticles with encapsulation of aPD1 were developed.•The nanoparticles had the ability to target melanoma and could increase the dose of aPD1 in tumor tissue.•The nanoparticles combined with PTT induced immunogenic environment in tumors and sensitized tumors to aPD1 therapy.
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